Treatment of language, behavior and social disorders

ABSTRACT

Methods of treating language, behavioral and social disorders are described, including methods of treating language disorders associated with electrographic abnormalities in the primary or associative language cortex of persons with autism spectrum disorders, pervasive developmental delay or acquired epileptic aphasia. A language, behavioral and social disorder may be treated by detecting epileptiform activity or an electrographic seizure for a subject&#39;s brain and applying neurostimulation to a language cortical region of the subject&#39;s brain (e.g., a primary or associative language cortical region). Detection of epileptiform activity or an electrographic seizure and stimulation of language cortex may be performed by a sensing and/or stimulation electrode that is inserted into a subject&#39;s brain and connected to one or more neurostimulation devices for monitoring and/or stimulating the language cortex.

BACKGROUND OF THE INVENTION

Language disorders may have psychological and physiological etiologies.For example, the autism spectrum disorders (autism, pervasivedevelopmental disorder, and acquired epileptic aphasia) are associatedwith language, behavior and social disability. These disabilities arebelieved to be a manifestation of electrographic and other functionaldisturbances in one or more language regions of the brain, as well asregions mediating behavior and social interaction skills. Persons withautism and pervasive developmental disorders, as well as acquiredepileptic aphasias such as Landau-Kleffner, have a high prevalence ofepilepsy and of epileptiform abnormalities.

Autism (sometimes called “classical autism”) is the most commoncondition in a group of developmental disorders known as the autismspectrum disorders. The Diagnostic and Statistical Manual of MentalDisorders (DSM-IV) defines autistic disorder as a syndrome withqualitative impairments in social interaction, communication, andrestricted and stereotyped patterns of behavior, interests andactivities. Autism varies widely in its severity and symptoms and may gounrecognized, especially in mildly affected children, or when masked bymore debilitating handicaps. Symptoms typically begin before age 3 andmay include problems using and understanding language; difficultyrelating to people, objects, and events; unusual play with toys andother objects; difficulty with changes in routine or familiarsurroundings, and repetitive body movements or behavior patterns.

Other autism spectrum disorders are characterized by delays in thedevelopment of socialization and communication skills. Asperger syndromeis an autism spectrum disorder characterized by a greater or lesserdegree of impairment in language and communication skills, as well asrepetitive or restrictive patterns of thought and behavior. Other autismspectrum disorders include Rett syndrome, childhood disintegrativedisorder and pervasive developmental disorder not otherwise specified(usually referred to as PDD-NOS).

Landau-Kleffner syndrome is the best-described syndrome of acquiredepileptic aphasia. This condition affects children, usually between theages of 3 and 7, who previously had no developmental, language, orinteractional difficulties. Subject's typically experience a ratherabrupt loss of language comprehension and expression, usually coincidentwith the onset of seizures and a profoundly abnormal sleep EEG.Electrographic status epilepticus (prolonged seizures) in sleep, orcontinuous spike-wave in slow-wave sleep is typical in acquiredepileptic aphasia and in the Landau Kleffner Syndrome (Trevathan E.,“Seizures and epilepsy among children with language regression andautistic spectrum disorders.” J Child Neurol 2004;19(S1):S49-57). Thecause for the aphasia in Landau-Kleffner syndrome is uncertain. Theseizures and the aphasia are believed to reflect abnormal brainfunctioning or the aphasia may be a consequence of the seizuredischarges.

Clinically evident seizures, as well as subclinical epileptiformdischarges and epileptiform electrographic abnormalities, may exacerbateor even cause the cognitive, language and behavior disorderscharacterizing the autism spectrum disorders and acquired epilepticaphasias. As many as 75% of children with autism haveelectroencephalogram (EEG) abnormalities and up to 46% have clinicalseizures (Hughes J R, Melyn M., “EEG and seizures in autistic childrenand adolescents: further findings with therapeutic implications.” ClinEEG Neurosci 2005;36(1):15-20; Hrdlicka M., Komarck V., Propper L.,Kulisck R., Zumrova A., Faladova L., Havlociocova M., Sedlacek Z.,Blainy M., Urbanek T., “Not EEG abnormalities but epilepsy is associatedwith autistic regression and mental functioning in childhood autism.”Eur Child Adolesc Psychiatry 2004;13(4):209-213; Tharp BR, “Epilepticencephalopathies and their relationship to developmental disorders: dospikes cause autism?” Ment Retard Dev Disabil Res Rev2004:10(2):132-134). The prevalence of epilepsy and epileptiformabnormalities in persons with autism spectrum disorders is highest inthose with moderate to severe retardation, motor deficits, severereceptive language deficits (Tuchman R., Rapin I., “Epilepsy in autism.”Lancet Neurol 2002;1 (6):352-358), early language regression (TrevathanE., “Seizures and epilepsy among children with language regression andautistic spectrum disorders.” J Child Neurol 2004; 19(S1):S49-57) orabnormal development during the first year of life. Epileptic seizuresare also associated with progressive regression in children with autism(Rossi P. G., Parmeggiani A., Bach V., Santucci M., Visconti P., “EEGfeatures and epilepsy in patients with autism.” Brain Dev1995;17(3):169-174).

Currently, there is no cure for autism spectrum disorders or acquiredepileptic aphasias. Therapies and behavioral interventions are designedto remedy specific symptoms. Treatment plans coordinate therapies andinterventions that target social interaction, verbal and nonverbalcommunication, and obsessive or repetitive routines and interests.Medications are used to address specific behavioral problems.Furthermore, we are not aware of any randomized clinical trials oftreatments for autistic language regression. Some persons with autismimprove cognitively when treated with antiepileptic drugs (AEDs).However, the potential for cognitive side effects limits AED use.

As an alternative or adjunct to medication, surgical interventions havealso been used as treatments. For example, vagus nerve stimulation (VNS)and multiple subpial transections, or cortical resection, have beenperformed to treat autism spectrum disorders. The impact of VNS onquality of life and alertness in 6 children with Landau-KleffnerSyndrome and 59 persons with autism was examined utilizing aretrospective subject outcome registry (Park Y. D., “The effects ofvagus nerve stimulation therapy on patients with intractable seizuresand either Landau-Kleffner syndrome or autism.” Epilepsy Behav2003;4(3):286-290). Fifty-eight percent of the subjects withLandau-Kleffner Syndrome and 78% of the subjects with autism reportedimproved quality of life and enhanced alertness. It is not possible todifferentiate whether these effects were related to reductions inseizures or to an independent mood effect given this study design.

Other surgical treatments include subpial transection. For example, asmall number of children with Landau-Kleffner syndrome who have notresponded to antiepileptic medications have been treated with subpialtransection (Nass R, Neville B. G., Harkness W. F., Cross J. H., Cass H.C., Burch V. C., Lees J. A., Taylor S. C., “Surgical treatment of severeautistic regression in childhood epilepsy.” Pediatr Neurol 1997; 16(2):137-140). This procedure severs interneuronal connections perpendicularto the trajectory of the cortical neuron. The procedure is performed inthe language area of the frontal lobe coincident with the maximalelectroencephalographic abnormalities. The procedure is thought toinhibit the propensity for abnormal electroencephalographic dischargesto propagate to adjacent neurons while preserving fiber tractssubserving motor and sensory function.

Thus, there is a need for treatments and systems for treating language,behavioral and/or social disorders, and particularly those related toautism, pervasive developmental disorders, and acquired epilepticaphasias. A system and method of using such a system could benefitindividuals with autism spectrum disorders and acquired epilepticaphasias, for which there is no effective treatment.

BRIEF SUMMARY OF THE INVENTION

Described herein are methods of treating language, behavioral and socialdisorders in a subject in need thereof. For example, methods of treatingautism spectrum disorders that have associated language, behavioral andsocial disorders are described. In general, language, behavioral and/orsocial disorders may be treated by applying stimulation to a languagecortical region (e.g., primary or associative language cortex) inresponse to epileptiform and other abnormal activity, in subjects inneed of treatment. In addition to primary or associative languagecortex, other neuronal regions may also be stimulated eithersimultaneously, or in sequence. Treatment may also include scheduledstimulation applied to a language cortical region (and other regions).Thus language, behavioral and social disorders related to autismspectrum disorders or acquired epileptic aphasias may be treated by anyof the responsive, scheduled, or responsive and scheduled stimulationmethods described herein. In particular, the methods for treatinglanguage disorders described herein may include the steps of detectingepileptiform activity in a subject's brain, and applyingneurostimulation to a primary and/or associative language corticalregion in response to the epileptiform activity.

Although many of the treatment methods and examples provided hereindescribe language disorders related to autism spectrum disorders oracquired epileptic aphasias, these methods may be used to treatbehavioral or social disorders as well. In some variations, language,behavioral and social disorders may be simultaneously treated. Themethods described herein may also be used to specifically treat abehavioral or social disorder. Any appropriate language disorder may betreated by the methods described herein, including language disordersrelated to autism spectrum disorders or acquired epileptic aphasias.

In many of the methods described herein, language disorders may betreated using a device that provides responsive and/or programmedelectrical stimulation to a subject's nervous system, particularlyneurological regions such as a primary or associative language cortex,the cingulate cortex, frontal cortical regions and other relevantportions of the brain and peripheral nervous system. In particular,language, behavioral and social disorders may be treated by applyingneurostimulation to one or more regions of the cerebral cortex mediatingbehavior and social interactions (e.g., cingulate, prefrontal, insula,or temporal cortex). One device described herein provides continuousmonitoring of electrocorticographic signals. Monitoring may take placethrough electrodes implanted into the brain (e.g., within specific brainregions). Monitoring can identify disturbances in brain electricalactivity (e.g., epleliptiform activity), which can direct therapy forthose subjects with abnormal electrocorticograms. Since electrographicdisturbances are likely to be dynamic, continuous monitoring may aid intimely and accurate intervention.

As described in more detail below, any appropriate brain region my bestimulated, particularly primary or associative language cortex, e.g.,Broca's area, Wemicke's area, the superior temporal sulcus, Heschl'sgyrus, planum polare, planum temporale, and/or the anterior superiorinsular cortices.

Responsive and/or scheduled stimulation of a subject's nervous system(which may be referred to as “neurostimulation”) may be applied to morethan one region of a subject's brain in addition to a language cortexregion. For example, stimulation may be applied to the cingulate cortex,prefrontal, insula, temporal cortex, or other regions of the cerebralcortex in response to abnormal electrographic activity (and/or at aprescheduled time). In addition to treating language disorders, thetreatment methods described herein may improve social and emotionaldisability in a subject, including subjects having autism spectrumdisorders or acquired epileptic aphasias.

In some variations, the step of applying neurostimulation comprisesapplying neurostimulation to a language area of the frontal lobe.Applying neurostimulation may involve applying neurostimulation to allor a part of the primary or associative language cortical region of thebrain coincident with the epileptiform activity or electrographicseizure. Detecting epileptiform activity or an electrographic seizuremay comprise detecting the activity from at least one electrodeimplanted in the brain. As described in more detail below, epileptiformactivity may be identified based on any appropriate characteristic. Forexample, when the activity is monitored by electrodes sensitive toneural electrical activity, epileptiform activity or an electrographicseizure may be identified by comparison with background electrographicactivity or based on characteristics of epileptiform activity andelectrographic seizures.

Any appropriate stimulation may be applied to treat a language,behavioral and/or social disorder, particularly electrical stimulation.For example, appropriate stimulation may comprise biphasiccharged-balanced pulses of 100 to 200 Hz frequency, 100-200 msecduration, pulse width of 100 μsec, and appropriate current necessary toachieve a charge density of 6 μC/cm² per phase. Different or variablestimulation may be used, e.g., depending on the response of the abnormalelectrographic activity. Stimulation can be adjusted to achieve thedesired response as follows: pulse width can be set between 40 to 1000microseconds, pulse frequency may be, for example, between 1 to 333 Hzand current can be adjusted between 0.5 and 12 milliamps. Theneurostimulation may be applied by one or more electrodes. In somevariations, when one or more electrodes are used to detect epileptiformactivity, the same electrode used to detect the epileptiform activity isalso used to apply neurostimulation. The neurostimulation applied mayfurther depend on the location of the electrodes (e.g., the brainregion), the level of activity, the time of day, the arousal state(e.g., asleep/awake status) of the subject, etc. The stimulation may bemodified to help the subject receive optimal stimulation with minimaladverse effects. It is reasonable to assume that individual subjectswill differ in terms of the optimal stimulus settings. Thus, thestimulation may be tailored to individual subjects, or it may be basedon characteristics taken from a population of subjects. In somevariations, the stimulation is the same for any subject. “Stimulation”is not limited to excitatory stimulation, but includes inhibitorystimulation as well.

As mentioned above, one or more electrodes may be used to detect and/ormeasure epileptiform activity or an electrographic seizure, and/or toapply neurostimulation. In some variations, the electrode or electrodesare implanted in the appropriate brain regions. For example, theelectrodes may be implanted in the cortex, or adjacent to the region ofinterest, such as a primary or associative language region. Implantedelectrodes (e.g., electrodes implanted into the subject's brain) mayrefer to electrodes that abut the region of interest (e.g., cortex)and/or electrodes that are inserted into the brain tissue. In somevariations, detecting epileptiform activity or an electrographic seizurein a subject comprises measuring the subject's EEG. Electrodes implantedin the subject's brain may be used. Electrodes external to the subject'sbrain may also be used. In some variations, scalp electrodes may be usedin addition to (or instead of) implanted brain electrodes.

As mentioned, a method of treating a language disorder may also involveapplying neurostimulation to a second brain region in response toepileptiform activity or an electrographic seizure. For example,neurostimulation may be applied to a second cortical region (e.g., thecingulate gyrus), in addition to a primary or associative languageregion.

A language, behavior or social disorder may also be treated by applyingneurostimulation at scheduled intervals to a cortical region mediatinglanguage, behavior, or social interaction. Stimulation can becontinuous, or applied for a set duration and with a set inter-stimulusinterval. In some variations, the method for treating a languagedisorder involves applying stimulation both in response to epileptiformactivity or an electrographic seizure, as well as at scheduledintervals. Scheduled intervals may be regularly scheduled (e.g., so thatneurostimulation can occur at pre-set times), or may be scheduled tooccur based on a subject's activity (e.g., when the subject is sleeping,etc.). Thus, in some variations, a neurostimulation may be scheduled tobe applied while the subject is sleeping.

Also described herein are methods of treating autism-related language,behavioral or social disorders in a subject in need thereof. Thesemethods include the steps of receiving electrical signals correspondingto a subject's neural (e.g., brain) electrical activity, detectingepileptiform activity or an electrographic seizure from the receivedelectrical signals, and applying neurostimulation to a primary orassociative language cortical region of the subject's frontal lobe inresponse to the epileptiform activity or an electrographic seizure. Thestep of receiving electrical signals corresponding to electricalactivity of a subject's brain may include receiving electrical activityfrom electrodes implanted in the subject's brain.

A neurostimulation device may be implanted so that at least a portion ofthe device is attached to the subject's cranium and includes one or moreleads having electrodes at the distal end of each lead. The electrodescan be placed within or against relevant regions of the brain in theform of a depth electrode or a subdural electrode. A single electrode ormultiple electrodes may be implanted. The device typically monitorsbrain activity, and may be configured to monitor electrical activity,changes in concentration of inhibitory or excitatory neurochemicals,changes in proteins or other gene products, or changes in temperature ormarkers of metabolic rate. Sensing electrodes are typically placed overthe cortical region of interest.

Optimal stimulation electrodes can be configured over time, as thesubject's symptoms and the effects of stimulation are observed.Stimulation may be quite focal, using adjacent electrodes as anode andcathode, or can be applied to multiple regions simultaneously byutilizing all of the electrodes of the device. Also, the electrodes overwhich neurostimulation is applied can be adjusted according to thesubject's short- and long-term response.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other objects, features, and advantages of the invention willbecome apparent from the detailed description below and the accompanyingdrawings, in which:

FIG. 1 is a block diagram illustrating one method for treating language,behavioral or social disorders as described herein.

FIG. 2A is a schematic illustration of an implantable neurostimulationdevice contacting various language cortical regions of a brain.

FIG. 2B shows a schematic illustration of a subject's head showingplacement of an implantable neutostimualtor.

FIG. 3 is a schematic illustration of a subject's cranium showing theimplantable neurostimulation device of FIG. 2 as implanted, including alead extending to the subject's brain.

FIG. 4 is a block diagram illustrating the operation of aneurostimulation device.

FIG. 5 is a block diagram illustrating subsystems of a neurostimulationdevice.

FIG. 6 is a block diagram illustrating components of a detectionsubsystem of a neurostimulation device as shown in FIG. 5.

FIG. 7 is a block diagram illustrating components of a waveform analyzerof the detection subsystem of FIG. 6.

FIG. 8 illustrates exemplary stimulation waveforms, as described herein.

DETAILED DESCRIPTION OF THE INVENTION

Described here are methods of treating language, behavioral and socialdisorders. In particular, methods of treating language disorders relatedto autism spectrum disorders or acquired epileptic aphasias aredescried. As mentioned previously, many of the treatment methodsprovided herein may be used specifically to treat language disorders.Behavioral or social disorders may also be treated by the methodsdescribed herein. In some variations, the methods described herein maybe used to treat a behavioral or social disorder, regardless of thepresence of a language disorder. As used herein, language disorders mayinclude language disorders related to autism spectrum disorders oracquired epileptic aphasias.

In general, a language, behavioral or social disorder may be treated bydetecting epileptiform activity or an electrographic seizure from thebrain 103, and applying neurostimulation to a primary or associativelanguage cortical region 102 of the brain, as illustrated schematicallyin FIG. 1. In the embodiment of the method shown in FIG. 1, a sensingand/or stimulation electrode is inserted into a subject's brain. Thesensing and/or stimulating electrodes are connected to one or moredevices for monitoring and/or stimulating the brain (e.g., languagecortex), referred to as neurostimulation devices. Examples andillustrations of the kinds of sensing and/or stimulation devices thatmay be used to treat language disorders are described in more detailbelow. Generally, these devices are configured to both detectepileptiform activity and/or an electrographic seizure in a subject'sbrain and apply neurostimulation. However, in some variations, separatedevices are used for monitoring brain activity and applyingneurostimulation.

Brain activity is monitored 103 so that epileptiform activity or anelectrographic seizure (actual activity or predicted epileptiformactivity or an electrographic seizure) can be detected. Activity may bedetected by comparing ongoing activity to typical epileptiform activity,including identifying characteristics of epileptiform activity or anelectrographic seizure from ongoing brain activity. This is described ingreater detail below. Once epileptiform activity or an electrographicseizure is detected, the subject's language cortex is stimulated 105. Insome variations, stimulation is provided at the location at or near thefocal brain region where the activity was detected. Appropriatestimulation is also described more fully below. Additional stimulationto secondary brain regions may be applied 107. For example, a secondarybrain region (e.g., cingulate gyrus) may also be simulated when (orbefore or after) the primary or associative language cortex isstimulated.

The methods for treating language, behavioral or social disordersdescribed herein may be used on any appropriate subject, particularlysubjects in need of treatment of a language disorder. For example,subjects (who may also be referred to as “patients”) may have autism,pervasive developmental disorders, and/or acquired epileptic aphasias.Examples and illustrations of the steps for treating subjects havingthese disorders are provided below, including exemplary devices andsystems that may be used as part of the treatment.

A. Insertion of a Sensing and/or Stimulation Device

Electrodes for sensing epileptiform activity or an electrographicseizure may be implanted into a subject's brain and connected to aneurostimulation device. Alternatively, electrodes may be attached tothe subject's head so that they detect activity through the skull andany intervening tissues. In some variations, the neurostimulation deviceto which electrodes are connected is affixed to the subject's skull. Theelectrodes may be configured as probes that are used to detect activity.Electrodes may be part of one or more electrical leads that connectseither directly or indirectly (e.g., wirelessly) to a neurostimulationdevice. In some variations, the same electrodes may be used both tosense activity and to apply neurostimulation.

One example of a device (e.g., a “neurostimulation device”) for sensingepileptiform activity or an electrographic seizure and applyingneurostimulation to a language region of the brain is shownschematically in FIG. 5, and illustrated in FIGS. 2A-4. This device issimilar to the devices illustrated in U.S. Patent ApplicationPublication No. 2006/0058856, and U.S. Pat. No. 6,810,285, both of whichare incorporated herein by reference in the entirety. It will beapparent that devices or systems for sensing epileptiform activity or anelectrographic seizure and for applying neurostimulation may be embodiedin a wide variety of forms. Consequently, the specific structural andfunctional details disclosed herein are representative and do not limitthe scope of the invention.

FIG. 2A illustrates, schematically, an implantable neurostimulationdevice 200 that is in communication with various regions of a subject'sbrain 201, 203, 205, particularly cortical language regions. FIG. 2shows a lateral surface of the cerebral hemisphere, including regionsidentified as important in language processing, formation andinterpretation, such as the opercular 205 and triangular gyri 201 (e.g.,Broca's area), and Wernicke's area 203. The variation of theneurostimulation device shown in this figure may receive signals fromthe subject's brain 209 and can respond by applying stimulation to thebrain regions (e.g., language cortical regions) where probes have beeninserted.

FIG. 2B depicts an intracranial implantation of a neurostimulationdevice 200 according to the invention, which in one embodiment is asmall self-contained responsive neurostimulator. As mentioned, aneurostimulation device (including a responsive neurostimulation device)may detect or predict neurological events, such as epileptiformelectrical activity, and may provide stimulation (e.g., electricalstimulation) to neural tissue in response to that activity, where thestimulation is specifically intended to treat a language disorder. Forexample, stimulation may be provided to terminate the epileptiformactivity or an electrographic seizure, to prevent epileptiform activity,or to prevent or lessen the effects or severity of language disordersassociated with (or caused by) epileptiform activity or anelectrographic seizure. The neurostimulation device may detectepileptiform activity or an electrographic seizure by any appropriatemethod.

A neurostimulation device may be capable of detecting or predictingepileptiform neurological events, as described more fully below.Preferably, neurological events representing epileptiform activity or anelectrographic seizure can be detected when they are actually occurring,in an onset stage, or as a predictive precursor before clinical symptomsbegin. The device may also be configured to detect and/or respond toother types of neurological activity, such as activity associated withmovement disorders (e.g. the tremors characterizing Parkinson'sdisease), migraine headaches, and chronic pain.

A neurostimulation device such as the device shown schematically inFIGS. 2A and 2B may be implanted intracranially in a subject's parietalbone 310, in a location anterior to the lambdoid suture 312 (see FIG.3). It should be noted, however, that the placement described andillustrated herein is merely exemplary, and other locations andconfigurations are also possible, in the cranium or elsewhere, dependingon the size and shape of the device and individual subject needs, orother factors. The device 200 is preferably configured to fit thecontours of the subject's cranium 314. In an alternative embodiment, thedevice 200 is implanted under the subject's scalp 212, but external tothe cranium. In yet another alternative embodiment, when it is notpossible to implant the device intracranially, it may be implantedpectorally (not shown), with leads extending through the subject's neckand between the subject's cranium and scalp, as necessary.

It should be recognized that the embodiment of the device 200 describedand illustrated herein is preferably a neurostimulation device fordetecting and treating language disorders (and related disorders) bydetecting epileptiform activity or an electrographic seizure (or itsonset or precursor activity) and applying neurostimulation to theappropriate brain region(s), thereby alleviating the disorder(s).Although the applicant believes that the stimulation of one or morelanguage areas of the brain before or during epileptiform activity or anelectrographic seizure may help treat language, behavioral or socialdisorders, the methods and systems described herein should not belimited to any particular theory of operation.

The neurostimulation device 200 may be any appropriate device capable ofdetecting neurological conditions and events (e.g., epileptiformactivity or an electrographic seizure) and performing actions inresponse thereto. The actions performed by the device 200 need not betherapeutic, but may involve data recording or transmission, providingwarnings to the subject, or any of a number of known alternativeactions. A neurostimulator may not be a single device, but may be asystem of component devices. For example, a detection device may signalto a separate stimulation device. Thus, a neurostimulation device mayalso act as a diagnostic device, and may be interfaced with externalequipment, as will be discussed in further detail below.

The intracranially implanted device 200 shown in FIG. 3 is affixed inthe subject's cranium 314 by way of a ferrule 316. The ferrule 316 is astructural member adapted to fit into a cranial opening, attach to thecranium 314, and retain the device 200. In one variation, the device 200is implanted by performing a craniotomy in the parietal bone 310anterior to the lambdoid suture 312 to define an opening 318 slightlylarger than the device 200. The ferrule 316 is inserted into the opening318 and affixed to the cranium 414, ensuring a tight and secure fit. Thedevice 310 is then inserted into and affixed to the ferrule 316.

As shown in FIG. 3, the device 200 includes a lead connector 320 adaptedto receive one or more electrical leads, such as a first lead 322. Thelead connector 320 acts to physically secure the lead 322 to the device200, and facilitates electrical connection between a conductor in thelead 322 coupling an electrode with circuitry within the device 200. Thelead connector 320 accomplishes this in a substantially fluid-tightenvironment with biocompatible materials.

A lead, including the lead 322 as illustrated in FIG. 3, is typically aflexible, elongated member having one or more conductors. As shown, thelead 322 is coupled to the device 200 via the lead connector 320, and isgenerally situated on the outer surface of the cranium 314 (and underthe subject's scalp 212), extending between the device 200 and a burrhole 324 or other cranial opening, where the lead 322 enters the cranium314 and is coupled to a depth electrode (e.g., one of the sensors512-518 of FIG. 5) implanted in a desired location in the subject'sbrain. If the length of the lead 322 is substantially greater than thedistance between the device 200 and the burr hole 324, any excess may beurged into a coil configuration under the scalp. As described in U.S.Pat. No. 6,006,124 to Fischell, et al., which is hereby incorporated byreference as though set forth in full herein, the burr hole 324 issealed after implantation to prevent further movement of the lead 322;in an embodiment of the invention, a burr hole cover apparatus isaffixed to the cranium 314 at least partially within the burr hole 324to provide this functionality.

The device 200 includes a durable outer housing 326 fabricated from abiocompatible material. Titanium, which is light, extremely strong, andbiocompatible, is used in analogous devices, such as cardiac pacemakers,and may serve advantageously in this context as well. As the device 200is self-contained, the housing 326 encloses a battery and any electroniccircuitry necessary or desirable to provide the functionality describedherein, as well as any other features. A telemetry coil may be in theinterior of the device 200 or provided outside of the housing 326 (andpotentially integrated with the lead connector 320) to facilitatecommunication between the device 200 and external devices.

The neurostimulation device configuration described herein andillustrated in FIG. 3 is self-contained, and may substantially decreasethe need for access to the device 200, allowing the subject toparticipate in normal life activities. Its small size and intracranialplacement causes a minimum of cosmetic disfigurement. The device 200will fit in an opening in the subject's cranium, under the subject'sscalp, with little noticeable protrusion or bulge. The ferrule 316 usedfor implantation allows the craniotomy to be performed and fit verifiedwithout the possibility of breaking the device 200, and also providesprotection against the device 200 being pushed into the brain underexternal pressure or impact. A further advantage is that the ferrule 316receives any cranial bone growth, so at explant, the device 200 can bereplaced without removing any bone screws—only the fasteners retainingthe device 200 in the ferrule 316 need be manipulated.

FIG. 5 shows a block diagram illustrating functional subsystems of anexemplary neurostimulation device. The implantable neurostimulationdevice 200 contains a memory subsystem 526 and a CPU 528, which can takethe form of a microcontroller. The memory subsystem is coupled to thedetection subsystem 522 (e.g., for receiving and storing datarepresentative of sensed EEG or other signals and evoked responses), thetherapy subsystem 524 (e.g., for providing stimulation waveformparameters to the therapy subsystem for electrical stimulation), and theCPU 528, which can control the operation of (and store and retrieve datafrom) the memory subsystem 526. In addition to the memory subsystem 526,the CPU 528 is also connected to the detection subsystem 522 and thetherapy subsystem 524 for direct control of those subsystems.

The device 200 may also include a communication subsystem 530, that maybe coupled to the memory subsystem 526 and the CPU 528. Thecommunication subsystem 530 enables communication between the device 200and the external environment, particularly an external programmer 412and a subject initiating device 424, both of which are described withreference to FIG. 4. FIG. 4 illustrates a system for controlling theneurostimulation device that may be used to treat language disorders.The communication subsystem 530 includes a telemetry coil (which may besituated inside or outside of the housing of an implantableneurostimulation device 200) enabling transmission and reception ofsignals, to or from an external apparatus, via inductive coupling.Alternative embodiments of the communication subsystem 530 could use anantenna for an RF link or an audio transducer for an audio link.Preferably, the communication subsystem 530 also includes a GMR (giantmagnetoresistive effect) sensor to enable receiving simple signals(namely the placement and removal of a magnet) from a subject initiatingdevice; this capability can be used to initiate signal recording.

Several support components may also be present in the neurostimulationdevice 200, including a power supply 532 and a clock supply 534. Thepower supply 532 supplies the voltages and currents necessary for eachof the other subsystems. The clock supply 534 supplies substantially allof the other subsystems with any clock and timing signals necessary fortheir operation, including a real-time clock signal to coordinateprogrammed and scheduled actions and the timer functionality used by thedetection subsystem 522.

In some variations of the invention the therapy subsystem 524 is coupledto a thermal stimulator 536 and a drug dispenser 538, thereby enablingtherapy modalities other than electrical stimulation. The device maytherefore include a stimulation output that may be a stimulationelectrode (which may be the same as a recording electrode), a drugdispenser outlet, or a thermal stimulation site (e.g., Peltier junctionor thermocouple), etc.

It should be observed that while the memory subsystem 526 is illustratedin FIG. 5 as a separate functional subsystem, the other subsystems mayalso require various amounts of memory to perform the functionsdescribed above and others. Furthermore, while the neurostimulationdevice 200 is preferably a single physical unit (i.e., a control module)contained within a single implantable physical enclosure, namely thehousing described above, other embodiments of the invention might beconfigured differently. The neurostimulation device 200 may be providedas an external unit not adapted for implantation, or it may comprise aplurality of spatially separate units each performing a subset of thecapabilities described above, some or all of which might be externaldevices not suitable for implantation. Also, it should be noted that thevarious functions and capabilities of the subsystems described hereinmay be performed by electronic hardware, computer software (orfirmware), or a combination thereof. The division of work between theCPU 528 and the other functional subsystems may also vary—the functionaldistinctions illustrated in FIG. 5 may not reflect the partitioning andintegration of functions in all systems or methods according to theinvention.

The neurostimulation device 200 shown in FIGS. 4 and 5 may be used formeasurement, detection and treatment. The device 200 is capable of beingcoupled to a plurality of sensors 512, 514, 516, and 518 (each of whichmay be individually or together connected to the neurostimulation device200 via one or more leads), which are shown as electrodes that may beused for both sensing and stimulation as well as the delivery of othertreatment modalities. In the illustrated embodiment, the coupling isaccomplished through a lead connector. Although four sensors are shownin FIG. 5, it should be recognized that any number is possible, and inthe embodiment described in detail below, eight electrodes are used assensors. In fact, it is possible to employ an embodiment of theinvention that uses a single lead with at least two electrodes, or twoleads each with a single electrode (or with a second electrode providedby a conductive exterior portion of the housing), although bipolarsensing between two closely spaced electrodes on a lead is preferred tominimize common mode signals including noise.

In one variation, the neurostimulation device 200 is capable ofreceiving two leads, each with four electrodes. One cortical lead andone depth lead, two cortical leads, or two depth leads can be usedsimultaneously to achieve the desired coverage of language cortex andother regions, (e.g., cingulate gyrus or other desired brain areas). Itwill be recognized that other embodiments of a system according to theinvention may receive more leads, or leads and sensors in differentforms than those specifically disclosed herein. As mentioned above, alead may have one or more electrodes.

The sensors 512-518 are in contact with the subject's brain (e.g., incontact with a language region of the subject's brain), or are otherwiseadvantageously located to receive EEG signals or provide electricalstimulation or another therapeutic modality. Each of the sensors 512-518is also electrically coupled to a sensor interface 520. Preferably, theelectrode interface is capable of selecting each electrode as requiredfor sensing and stimulation; accordingly the electrode interface iscoupled to a detection subsystem 522 and a therapy subsystem 524 (whichmay provide electrical stimulation and other therapies). The sensorinterface 520 may also provide any other features, capabilities, oraspects, including but not limited to amplification, isolation, andcharge-balancing functions, that are required for a proper interfacewith neurological tissue and not provided by any other subsystem of thedevice 200.

Once a neurostimulation device has been attached to electrodes implantedinto the subject's brain (particularly language cortex), a languagedisorder may be treated by monitoring brain activity to detectepileptiform activity or an electrographic seizure. As mentioned herein,a neurostimulation device may be an integrated device, so that that theelectrodes do not need to be separately attached.

B. Detection of Epileptiform Activity or an Electrographic Seizure

In general, epileptiform activity or electrographic seizures may bedetected by monitoring electrical activity of the subject's brain. Inone variation, electrographic signals are received by electrodes andanalyzed. Epileptiform activity or an electrographic seizure may berecognized by comparing received signals, or characteristics derivedfrom received signals, with signals or characteristics correlated toepileptiform activity or an electrographic seizure. The signals andcharacteristics correlated with epileptiform activity or anelectrographic seizure may be derived from population data, or based onactivity or characteristics derived from the specific subject into whomthe neurostimulation device has been implanted. Furthermore, thedetection of epileptiform activity or electrographic seizures may bemodifiable (e.g., learned).

For example, the detection subsystem 522 of the device 200 may includean EEG waveform analyzer. Detection is generally accomplished inconjunction with a central processing unit (CPU) 528. The waveformanalyzer is adapted to receive signals from the sensors 512-518 (e.g.,electrodes), through the sensor interface (i.e., lead connector) 520,and to process those EEG signals to identify epileptiform activity or anelectrographic seizure. One way to implement such EEG analysisfunctionality is disclosed in detail in U.S. Pat. No. 6,016,449 toFischell et al., incorporated by reference above. Additional methods aredescribed in U.S. Pat. No. 6,810,285, relevant details of which will beset forth below (and which is also hereby incorporated by reference asthough set forth in full). The detection subsystem may optionally alsocontain further sensing and detection capabilities, including but notlimited to parameters derived from other physiological conditions (suchas electrophysiological parameters, temperature, blood pressure,neurochemical concentration, etc.). In general, prior to analysis, thedetection subsystem performs amplification, analog to digitalconversion, and multiplexing functions on the signals in the sensingchannels received from the sensors 512-518.

A neurostimulation device may monitor brain activity and detectepileptiform activity or electrographic seizures (or the onset ofepileptiform activity or an electrographic seizure) in any appropriatemanner. For example, an implantable neurostimulation device may employ acombination of signal processing and analysis modalities, and may reducedata by extracting characteristics or features from the monitored brainactivity. For example, a neurostimulation device may extract featuressuch as: line length function (representing sample to sample amplitudevariability of an EEG signal within a time window), area function(representing the total deviation of the EEG signal from non-zero over atime window), half waves (representing the interval between a localwaveform minimum and a local waveform maximum), and the like. Extractedfeatures may be compared to features that may indicate (individually orin the aggregate) epileptiform activity or an electrographic seizure.For example, line length functions, area functions and/or half waves mayfall within a range suggestive or indicative of epileptiform activity oran electrographic seizure. Additional features or characteristics ofepileptiform activity or an electrographic seizure may be extracted aswell. As mentioned above, these ranges may be preset or modifiable, andmay be tailored to a specific subject. Thus, there may be a period of“learning” to determine characteristics correlated to epileptiformactivity or an electrographic seizure. In some variations, the range offeatures may be learned, or additional features may be added to theneurostimulation device.

Epileptiform activity is distinguished from a patient's typicalelectrographic background by virtue of its sudden onset, morphology,frequency and amplitude. A typical epileptiform discharge is a spikewave. A spike is a sharply contoured wave, typically of less than 200msec duration. Other common epileptiform discharges are sharp waves, andpolyspike waves. Electrographic seizures (which may or may not beaccompanied by neurological changes) arise from the backgroundelectrographic activity, and are usually characterized by abnormallyorganized activity which evolves spatially and over time. The waveformsmay be spike or sharp waves, or may be rhythmic and high amplitude deltawaves (1 to 4 Hz) or even very low amplitude waves of frequencies inexcess of 20 to 25 Hz. A physician trained in electroencephalography isable to identify both epileptiform activity and electrographic seizures.

For example, U.S. Pat. No. 6,353,754 (herein incorporated by referencein its entirety) also provides an example of how epileptiform activitymay be recognized in an individual subject by developing an optimizedset of subject-specific parameters. Brain activity may be recorded overa period of time in which epileptiform activity or an electrographicseizure occurs, and recordings of the activity during epileptic activitymay be marked. Computer analysis of this activity can determinewaveforms that are characteristic of epileptic activity specific for theindividual subject. By comparing ongoing brain activity measured usingthe same device, epileptiform activity or an electrographic seizure canbe detected, and therefore used in the treatments described herein.

FIG. 6 illustrates details of a detection subsystem 522 such as thesubsystem shown in FIG. 5. Inputs from the electrodes (sensors 512-518)are on the left, and connections to other subsystems are on the right.Signals received from the sensors 512-518 (as routed through the sensorinterface 520) are received in an input selector 610. The input selector610 allows the device to select which electrodes or other sensors (ofthe sensors 512-518) should be routed to which individual sensingchannels of the detection subsystem 522, based on commands receivedthrough a control interface 618 from the memory subsystem 526 or the CPU528 (FIG. 5). Preferably, when electrodes are used for sensing, eachsensing channel of the detection subsystem 522 receives a bipolar signalrepresentative of the difference in electrical potential between twoselectable electrodes. Accordingly, the input selector 610 providessignals corresponding to each pair of selected electrodes to a sensingfront end 612, which performs amplification, analog to digitalconversion, and multiplexing functions on the signals in the sensingchannels.

A multiplexed input signal representative of all active sensing channelsis then fed from the sensing front end 612 to a waveform analyzer 614.The waveform analyzer 614 is preferably a special-purpose digital signalprocessor (DSP) adapted for use with the invention, or in an alternativeembodiment, may comprise a programmable general-purpose DSP. In thedisclosed embodiment, the waveform analyzer has its own scratchpadmemory area 616 used for local storage of data and program variableswhen the signal processing is being performed. In either case, thesignal processor performs suitable measurement and detection methodsdescribed generally above and in greater detail below. Any results fromsuch methods, as well as any digitized signals intended for storagetransmission to external equipment, are passed to various othersubsystems of the device 200, including the memory subsystem 526 and theCPU 528 (FIG. 5) through a data interface 620. Similarly, the controlinterface 618 allows the waveform analyzer 614 and the input selector610 to be in communication with the CPU 528. The waveform analyzer 614is illustrated in detail in FIG. 7.

In the exemplary waveform analyzer illustrated in FIG. 7, theinterleaved digital data stream representing information from all of theactive sensing channels is first received by a channel controller 710.The channel controller applies information from the active sensingchannels to a number of wave morphology analysis units 712 and windowanalysis units 714. It is preferred to have as many wave morphologyanalysis units 712 and window analysis units 714 as possible, consistentwith the goals of efficiency, size, and low power consumption necessaryfor an implantable device. In one embodiment, there are sixteen wavemorphology analysis units 712 and eight window analysis units 714, eachof which can receive data from any of the sensing channels of thesensing front end 612 (FIG. 6), and each of which can be operated withdifferent and independent parameters, including differing sample rates.

Each of the wave morphology analysis units 712 operates to extractcertain feature information from an input waveform. Similarly, each ofthe window analysis units 714 performs certain data reduction and signalanalysis within time windows. Output data from the various wavemorphology analysis units 712 and window analysis units 714 are combinedvia event detector logic 716. The event detector logic 716 and thechannel controller 710 are controlled by control commands 718 receivedfrom the control interface 618 (FIG. 6).

A “detection channel,” as the term is used herein, refers to a datastream including the active sensing front end 612 and the analysis unitsof the waveform analyzer 614 processing that data stream, in both analogand digital forms. It should be noted that each detection channel canreceive data from a single sensing channel; each sensing channelpreferably can be applied to the input of any combination of detectionchannels. The latter selection is accomplished by the channel controller710. As with the sensing channels, not all detection channels need to beactive; certain detection channels can be deactivated to save power orif additional detection processing is deemed unnecessary in certainapplications.

In conjunction with the operation of the wave morphology analysis units712 and the window analysis units 714, a scratchpad memory area 616 isprovided for temporary storage of processed data. The scratchpad memoryarea 616 may be physically part of the memory subsystem 526 (FIG. 5), oralternatively may be provided for the exclusive use of the waveformanalyzer 614 (FIG. 6). Other subsystems and components of aneurostimulation device (or system including a neurostimulation device)may also be furnished with local scratchpad memory, if such aconfiguration is advantageous.

A neurostimulation device may also operate in conjunction with externalequipment. For example, in variations in which subject-specifictemplates (indicative of epileptiform activity or an electrographicseizure) are used, the device may communicate with one or moreprogramming devices configured to receive and analyze brain activityfrom the device, and receive instructions or detection parameters (e.g.,a detection template) to assist in determining epileptiform activity oran electrographic seizure.

Returning now to FIG. 4, a neurostimulation device 200 may be mostlyautonomous (particularly when performing its usual sensing, detection,and stimulation capabilities), but may include a selectable part-timewireless link 410 to external equipment such as a programmer 412. Thewireless link 410 is established by moving a wand (or other apparatus)having communication capabilities and coupled to the programmer 412 intocommunication range of the neurostimulation device 200 (for example, animplantable neurostimulation device). The programmer 412 can then beused to manually control the operation of the device, as well as totransmit information to or receive information from the neurostimulationdevice 200.

The programmer 412 may perform a number of operations. In particular,the programmer 412 may specify and set variable parameters in theimplantable neurostimulation device 200 to adapt the function of thedevice to meet the subject's needs, upload or receive data (includingbut not limited to stored EEG waveforms, parameters, or logs of actionstaken) from the neurostimulation device 200 to the programmer 412,download or transmit program code and other information from theprogrammer 412 to the neurostimulation device 200, or command theneurostimulation device 200 to perform specific actions or change modesas desired by a physician operating the programmer 412. To facilitatethese functions, the programmer 412 may be adapted to receive clinicianinput 414 and provide clinician output 416; data is transmitted betweenthe programmer 412 and the neurostimulation device 200 over the wirelesslink 410.

The programmer 412 may be used at a location remote from theneurostimulation device 200 if the wireless link 410 is enabled totransmit data over long distances. For example, the wireless link 410may be established by a short-distance first link between theneurostimulation device 200 and a transceiver, with the transceiverenabled to relay communications over long distances to a remoteprogrammer 412, either wirelessly (for example, over a wireless computernetwork) or via a wired communications link (such as a telephoniccircuit or a computer network).

The programmer 412 may also be coupled via a communication link 418 to anetwork 420 such as the Internet. This allows any information uploadedfrom the neurostimulation device 200, as well as any program code orother information to be downloaded to the neurostimulation device 200,to be stored in a database 422 at one or more data repository locations(which may include various servers and network-connected programmerslike the programmer 412). This would allow a subject (and the subject'sphysician) to have access to important data, including past treatmentinformation and software updates, essentially anywhere in the worldwhere there is a programmer (like the programmer 412) and a networkconnection. Alternatively, the programmer 412 may be connected to thedatabase 422 over a trans-telephonic link.

In one embodiment, the neurostimulation device 200 is also adapted toreceive communications from an initiating device 424, typicallycontrolled by the subject or a caregiver. Accordingly, subject input 426from the initiating device 424 is transmitted over a wireless link tothe neurostimulation device 200; such subject input 426 may be used tocause the neurostimulation device 200 to switch modes (on to off andvice versa, for example) or perform an action (e.g., store a record ofEEG data). Preferably, the initiating device 424 is able to communicatewith the neurostimulation device 200 through a communication subsystem530 (FIG. 5), and possibly in the same manner the programmer 412 does.The link may be unidirectional (as with the magnet and GMR sensordescribed below), allowing commands to be passed in a single directionfrom the initiating device 424 to the neurostimulation device 200, butin an alternative embodiment of the invention is bi-directional,allowing status and data to be passed back to the initiating device 424.Accordingly, the initiating device 424 may be a programmable PDA orother hand-held computing device, such as a PALM device or POCKETPC.However, a simple form of initiating device 424 may take the form of apermanent magnet, if the communication subsystem 530 (FIG. 5) is adaptedto identify magnetic fields and interruptions therein as communicationsignals.

In an embodiment of the invention, the programmer 412 may be acommercially available PC, laptop computer, or workstation having a CPU,keyboard, mouse and display, and running a standard operating systemsuch as Microsoft WINDOWS, LINUX, UNIX, or APPLE MAC OS. A dedicatedprogrammer apparatus with a custom software package (which may not use astandard operating system) could be developed. The programmer 412 canprocess, store, play back and display on the display the subject's EEGsignals, as previously stored by the neurostimulation device 200 of theneurostimulation device.

The computer workstation software operating program may also have thecapability to simulate the detection and prediction of epileptiformactivity or an electrographic seizure and other symptoms of patientdisorders. Thus, the software operating program of the present inventionmay allow a clinician to create or modify a subject-specific collectionof information comprising algorithms and algorithm parameters fordetecting epileptiform activity or an electrographic seizure. Thesubject-specific collection of detection algorithms and parameters maybe referred to herein as a detection template or subject-specifictemplate. The subject-specific template, in conjunction with otherinformation and parameters generally transferred to the implanted device(such as stimulation parameters, time schedules, and othersubject-specific information), make up a set of operational parametersfor the neurostimulation device.

As mentioned briefly above, epileptiform activity or an electrographicseizure may be detected at any appropriate region of the brain. Forexample epileptiform activity or an electrographic seizure may bedetected by EEG measurements (brain electrical activity measurement)from electrodes implanted in the brain. In particular, epileptiformactivity or an electrographic seizure may be detected using electrodesadjacent to a region of the cortex associated with language, such as theprimary or associative language cortex. In some variations, epileptiformactivity or an electrographic seizure is detected from outside of thebrain (e.g., using scalp electrodes).

Language, behavioral, or social dysfunction in persons with an autismspectrum disorder, pervasive developmental delay or acquired epilepticaphasia may be treated by applying neurostimulation in response to theepileptiform activity or an electrographic seizure. The stimulationapplied may be related to the epileptiform activity or an electrographicseizure detected. For example, in some variations, the activity (e.g.,epileptiform activity or an electrographic seizure) detected from thesubject's brain is graded or qualified. For example, the severity orintensity of the epileptiform activity or an electrographic seizuremaybe classified, and this classification may be used to determine theneurostimulation applied in response to the epileptiform activity or anelectrographic seizure.

C. Applying Neurostimulation to Primary or Associative Language Cortex

After the identification of epileptiform activity (or the onset ofepileptiform activity) or electrographic seizure, a cortical languageregion of the subject's brain is stimulated. Stimulation of primary orassociative language cortex in response to epileptiform activity or anelectrographic seizure of the brain may improve or protect againstlanguage disability. As described above, the same neurostimulationdevice used to detect epileptiform activity or an electrographic seizuremay be used to apply stimulation, or a different neurostimulation devicemay be used. Any appropriate stimulation may be used. Although theexamples described herein involve electrical stimulation, other (oradditional) types of stimulation may be used. For example, stimulationmay be electrical, chemical, thermal, or the like (or some combinationthereof).

As mentioned briefly above, the type and amount of neurostimulationapplied may be determined or graded based on the type and/or intensityof epileptiform activity or an electrographic seizure detected. Forexample, the intensity of neurostimulation may be correlated to theintensity of the epileptiform activity or an electrographic seizure(e.g., prolonged epileptiform activity may trigger prolongedneurostimulation). In some variations, the type of neurostimulationapplied may also be regulated. For example, epileptiform activity or anelectrographic seizure may trigger predominantly inhibitorneurostimulation of language cortex, or predominantly excitatoryneurostimulation of language cortex, or a combination of both. In onevariation, stimulation (neurostimulation) is biphasic, charge-balancedpulses of 100 to 200 Hz, 100 to 200 msec duration, pulse width of about160 μsec, and have a current maximized to tolerability, or begun at acurrent sufficient to achieve a charge density of 6 μC/cm2 per phase.

A neurostimulator may provide electrical neurostimulation by applyingelectrical energy to electrodes within or adjacent to language cortex.As mentioned above, a neurostimulation device may include one or moreleads, and each lead may have multiple electrodes. Leads and/orelectrodes may be adapted to record from and/or apply energy to languagecortex. For example, the lead may be a planar electrode having surfaceelectrodes for abutting language cortex. In some variations, leadsconform to the shape of language cortex or adjacent regions (e.g., sulciand/or gyri) on the brain surface. Leads may further be adapted toanchor to the correct language cortex area. For example, leads maycomprise surface adhesive and/or cortical anchors.

A neurostimulation device may also include one or more subsystems forcontrolling and applying neurostimulation. For example, theneurostimulation device 200 shown in FIG. 5 includes a therapy subsystem524 that is capable of applying electrical stimulation (or othertherapies) to neurological tissue. Stimulation may be in the form of asubstantially continuous stream of pulses, or pulses delivered on ascheduled basis. Thus, therapeutic electrical stimulation may beprovided in response to epileptiform events or conditions detected bythe waveform analyzer function of the detection subsystem 522. Asillustrated in FIG. 5, the therapy subsystem 524 and the EEG analyzerfunction of the detection subsystem 522 are in communication; thisfacilitates the ability of therapy subsystem 524 to provide responsiveelectrical stimulation and/or other therapies, as well as an ability ofthe detection subsystem 522 to blank the amplifiers while electricalstimulation is being performed to minimize stimulation artifacts. It iscontemplated that the parameters of a stimulation signal (e.g.,frequency, duration, waveform) provided by the therapy subsystem 524would be specified by other subsystems in the device 200, and may bespecific to the language cortex.

Examples of stimulation waveforms are shown in FIG. 8. In addition tobiphasic pulse waveforms, other wave morphologies may have advantageousapplications herein. A sinusoidal stimulation signal 810 can be used forscheduled or responsive brain stimulation. In general, sinusoidal andquasi-sinusoidal waveforms may be delivered at low frequencies to havean inhibitory effect, where low frequencies are 0.5 to 10 Hz deliveredfor 0.05 to 60 minutes at a time. Such waveforms may be applied as aresult of determining that inhibition is desired on a scheduled basis,or after conditions indicate that responsive stimulation should beapplied. Higher frequency sinusoidal or quasi-sinusoidal waveforms maybe used for activation. Amplitudes in the range of 0.1 to 10 mA wouldtypically be used, but attention to safe charge densities is importantto avoid neural tissue damage (where a conservative limit is 25 μC/cm²per phase). It should be noted that the inhibitory and activatingfunctions of various sinusoidal stimulation parameters may vary whenapplied to different parts of the brain; the above is merely exemplary.

Sinusoidal and quasi-sinusoidal waveforms presented herein may beconstructed digitally by the therapy subsystem 524 (FIG. 5) of theneurostimulation device 200. As a result, the sinusoid 810 is reallygenerated as a stepwise approximation, via a series of small steps 812.The time between steps is dependent upon the details of the waveformbeing generated. It is anticipated that the stair step waveform 812 maybe filtered to arrive at a waveform more similar to 814, which wouldallow for longer periods of time between steps, and for larger steps.Likewise, for the waveforms 816, 820, and 822 (described below), it isassumed that they may be created with a series of steps notwithstandingtheir continuous appearance in the figures.

A truncated ramp waveform is also possible, where the rate of the ramp,the amplitude reached and the dwell at the extreme are all selectableparameters. The truncated ramp has the advantage of ease of generationwhile providing the physiological benefits of a sinusoidal orquasi-sinusoidal waveform.

A variable sinusoidal waveform 816 (where the amplitude and frequencyare varied while the waveform is applied) is also illustrated. The rateand amplitude of the variation may be varied based upon a predefinedplan, or may be the result of the implanted neurostimulation devicesensing signals from the brain during application or betweenapplications of the waveform, and adjusting to achieve a particularchange in the sensed signals. The variable waveform 816 is illustratedherein as having a positive direct current component, but it should benoted that this waveform, as well as any of the others described hereinas suitable for use according to the invention, may or may not beprovided with a direct current component as clinically desired.

Waveforms 820 and 822 depict variations where the stimulating waveformis generated having a largely smooth waveform, but having the additionalfeature where the interval between waveforms is set by varying aselectable delay, as would be used with the traditional biphasic pulsewaveforms described previously. In waveform 820, the stimulatingwaveforms are segments of a sine wave separated in time (of course thesame technique could be used for the truncated ramp or other arbitrarymorphologies). Waveform 822 shows a variation where the derivative intime of the waveform approaches zero as the amplitude approaches zero.The particular waveform 822 is known as a haversine pulse.

Although the term “haversine pulse” is useful to describe the waveformof 822, it should be noted that all of the waveforms represented in FIG.8 are considered herein to be generally “non-pulsatile,” in contrastwith waveforms made up of traditional discontinuous (e.g. square)pulses. As the term is used herein, “non-pulsatile” can also be appliedto other continuous, semi-continuous, discontinuous, or stepwiseapproximated waveforms that are not exclusively defined by monophasic orbiphasic square pulses.

In some variations, the default stimulation provided by aneurostimulation device is to stimulate with charge-balanced biphasicpulses. This stimulation may be generated by hardware that automaticallygenerates a symmetric equal-current and equal-duration butopposite-polarity pulse as part of every stimulation pulse; the precisecurrent control enabled by the present invention makes this approachpossible. However, the neurostimulation device is preferablyprogrammable to disable the automatic charge balancing pulse, therebyenabling the application of monophasic pulses (of either polarity) andother unbalanced signals.

Alternatively, charge balancing can be accomplished using software byprogramming the neurostimulation device to specifically generatebalancing pulses or signals of opposite phase. Regardless of whethercharge balancing is accomplished through hardware or software (or acombination thereof), it is not necessary for each individual pulse orother waveform component to be counteracted by a signal with identicalmorphology and opposing polarity; symmetric signals are not alwaysnecessary. It is also possible, when charge balancing is desired, tocontinuously or periodically calculate the accumulated charge in eachdirection and ensure that the running total is at or near zero over arelatively long term and preferably, that it does not exceed a safetythreshold even for a short time.

To minimize the risks associated with waveforms that are eitherunbalanced or that have a direct current component, it is advantageousto use electrodes having enhanced surface areas. This can be achieved byusing a high surface area material like platinum black or titaniumnitride as part or all of the electrode. Some experimenters have usediridium oxide advantageously for brain stimulation, and it could also beused here (see, e.g., Weiland and Anderson, “Chronic Neural Stimulationwith Thin-Film, Iridium Oxide Electrodes,” IEEE Transactions onBiomedical Engineering, 47: 911-918 (2000).

Referring back to FIG. 1, in some methods for treating languagedisorders, a second brain region may also be stimulated 107 in additionto language cortex in response to epileptiform activity or anelectrographic seizure. For example, in some variations, detection ofepileptiform activity or an electrographic seizure causes theneurostimulation device to stimulate language cortex and also one ormore additional cortical regions (e.g., the cingulate cortex) ornon-cortical regions of the nervous system. The stimulation applied tothe second region may be the same stimulation applied to the languagecortex, or it may be different. For example, the stimulus applied to thesecond region may be excitatory or inhibitory (or a mix of excitatoryand inhibitory) independent of the stimulus applied to language cortex.In some variations the stimulus applied to the language cortex and thesecond region are different modalities (e.g., electrical and thermal orchemical, etc.). In some variations, the timing of the stimulation tothe language cortex and the second region are different. For example,the stimulation of the second region may be delayed by some amount oftime from the stimulation of language cortex, or may be shorter orlonger in duration.

In some variations, the method of treating language, behavior and socialdisorders (e.g., associated with autism, pervasive developmentaldisorders and acquired epileptic aphasias) may also include applyingneurostimulation to primary and/or associative language cortex and toother regions (such as the cingulated and prefrontal cortex) atscheduled intervals. Thus, neurostimulation is applied at predeterminedtimes or predetermined intervals, even in the absence of detectedepileptiform activity or an electrographic seizure. For example, in onevariation, the neurostimulation device applies multiple episodes ofneurostimulation to language cortex at regular intervals. The timeduring which such “un-triggered” stimulation is applied may bescheduled, so that it may occur at the same time every day, or inresponse to the subject's activity. For example, un-triggeredstimulation may be scheduled to occur when the subject is sleeping orwhen the subject is awake. Sleep or arousal may be determined based on atime schedule, based on the subject's brain activity, or based on thesubject's metabolic activity. Thus, the stimulus applied to treat alanguage disorder may depend upon the arousal state of the subject. Forexample, the intensity and/or duration of a stimulus may be greater orlesser when the subject is sleeping. Since the arousal state of thesubject may have effects on the subject's processing and response tolanguage stimulus, it may be beneficial to tailor the response to thesubject's arousal state.

In some variations, detection of epileptiform activity or anelectrographic seizure initiates the application of a regime ofneurostimulation of language cortex. For example, detection ofepileptiform activity or an electrographic seizure may trigger a seriesof stimulation. The series may include stimulation (e.g., excitatory,inhibitory, or a combination) spread out over time. Thus, a stimulustrain may be triggered where stimulation is separated by apre-determined time period (e.g., milliseconds, seconds, minutes, hours,etc.). In some variations a pattern of epileptiform activity or anelectrographic seizure may trigger a regime of neurostimulation. Forexample, two or more episodes of epileptiform activity or anelectrographic seizure within a pre-set time period (e.g., milliseconds,seconds, minutes, hours) may trigger application of a series of stimuluswaveforms or pulses to the language cortex.

As mentioned briefly above, the neurostimulation device may also beconfigured to allow the subject or physician to manually apply stimulusto the language cortex. Furthermore, audio, visual, or tactile signalsmay be provided to the subject to provide feedback from the device. Insome variations, the method of treating a subject for a languagedisorder may include one or more feedback steps, in which the subject orpractitioner (e.g., physician, technician, etc.) provides feedback toadjust the stimulation applied to the language region or regions of thesubject's brain. The intensity of stimulation applied by theneurostimulation device may be increased or decreased based on thesubject's condition.

The methods and systems for treating language disorders described hereinmay include multiple modalities of therapy such as response stimulation(e.g., stimulation triggered by epileptiform activity or anelectrographic seizure) and scheduled stimulation. In general, regularor scheduled therapy may be considered advantageous at certain times,and may be scheduled to operate in parallel with responsive therapymodes. Moreover, the neurostimulation device 200 may also gather data toenable therapy refinement in connection with the programmer 412 (FIG. 4)and other external equipment.

A subject may be treated for a language disorder by applying thetreatment methods described herein. A subject in need of treatment of alanguage disorder may include a subject having autism, pervasivedevelopmental disorders, and/or acquired epileptic aphasias.

An exemplary method for treating a language disorder associated withautism, pervasive developmental disorder or acquired epileptic aphasiasmay include the step of implanting a device for detecting epileptiformactivity or an electrographic seizure. In some variations, anon-responsive (e.g., un-triggered) stimulation is first applied to thesubject's language cortex. This therapy may include electricalstimulation as discussed herein. This initial course of therapy may becontinued until improvement is observed, or for some pre-determinedperiod of time. Following the initial course of therapy, theneurostimulation device may be used to process inputs and monitor brainactivity by receiving electrical signals corresponding to the electricalactivity of the subject's brain. Electrographic activity may beanalyzed. If epileptiform electrographic activity is detected from theobserved electrical activity, then an appropriate neurostimulation isapplied to language cortex (e.g., the primary or associative languagecortical region of a subject's brain). Monitoring may be continuous. Forexample, after a first epileptiform activity or an electrographicseizure is detected and language cortex is stimulated, the monitoringcontinues until the device is removed or disabled (e.g., by the subjector medical professional). In some variations the monitoring is notcontinuous, but can be turned on or off, or scheduled to turn on or off.

While the foregoing detailed description of various embodiments of thepresent invention are set forth in some detail, the invention is notlimited to those details. The methods and systems for treating language,behavioral and/or social disorders according to the invention can differfrom the disclosed embodiments in numerous ways. In particular, it willbe appreciated that the methods described herein may include one or moreadditional steps for treating language disorders, including languagedisorders associated with the autism spectrum disorders, pervasivedevelopmental delay and acquired epileptic aphasias. Furthermore, themethods may be used as part of treatments of disorders encompassing butnot limited to language disorders. It will be appreciated that thefunctions disclosed herein as being performed by hardware and software,respectively, may be performed differently in an alternative embodiment.It should be further noted that functional distinctions are made abovefor purposes of explanation and clarity; structural distinctions in asystem or method according to the invention may not be drawn along thesame boundaries.

What is claimed is:
 1. A method of treating a language disorder in ahuman patient, comprising: continuously monitoring with an implantedresponsive neurostimulator electrical signals sensed from a first regionof the patient's brain related to the language disorder during aselected period when the patient is experiencing a stage of sleep;detecting in the continuously monitored electrical signals with theneurostimulator the occurrence of one or more of the following events:epileptiform activity that causes a language disorder, and anelectrographic seizure that causes a language disorder; responding tothe occurrence of the one or more events by applying neurostimulationfrom the neurostimulator to a second region of the patient's brain fortreating the language disorder, wherein the second region is a primaryor associative language cortical region; and responding to theoccurrence of the one or more events by applying neurostimulation fromthe neurostimulator to a third region of the patient's brain fortreating the language disorder, wherein the third region is differentfrom both the first and second region.
 2. The method of claim 1, whereincontinuously monitoring electrical signals sensed from a first region ofthe patient's brain further includes continuously monitoring electricalsignals sensed by at least one electrode implanted in or adjacent thefirst region.
 3. The method of claim 2, wherein responding to thedetection of the one or more events by applying neurostimulation to thesecond region of the patient's brain further includes deliveringstimulation through at least one electrode implanted in or adjacent thesecond region.
 4. The method of claim 1, wherein the first region andthe second region are the substantially the same region.
 5. The methodof claim 1, wherein the third brain region is selected from the groupconsisting of: the cingulate gyms and a non-cortical region of thenervous system.
 6. The method of claim 1, further comprising applyingneurostimulation to at least one of the first, second and third regionsat a plurality of scheduled intervals during the selected period even inthe absence of an occurrence of the one or more events.